This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lipoproteins transport cholesterol and triglycerides throughout the extracellular spaces of the body. Small disc-shaped lipoproteins containing apolipoprotein A-I and apolipoprotein (apo) E play in a major role in reverse cholesterol transport, a mechanism by which cholesterol is removed from atherosclerotic lesions. ApoE-containing lipoproteins also play a key role in transporting lipid during neuronal development and repair. Although lipid-free structures of both apoA-I and apoE have been determined by x-ray crystallography, there is a lack of detailed structural information of either apolipoprotein associated with lipid in their physiologically relevant states. To fill this void, we have crystallized model apoA-I lipoproteins that are active in reverse cholesterol transport that diffract to 20 and physiologically active apoE lipoproteins that diffract to 8 We are also continuing our studies of lipid-free apoE. It has been recently shown that intracellular cleavage of the COOH-terminal domain of lipid-free apoE is associated cytoskeletal disruption and the type of neuronal cell death characteristic of Alzheimer's disease. Since the structure of the COOH-terminal domain is unknown, we are determining the structure of the toxic fragment (residues 223-272) and the intact COOH-terminal domain in order to understand the structural basis of the fragment's cellular toxicity. As an outgrowth of our interest in apoE, we also working on the structure of receptor associated protein (RAP). RAP is a chaperone that is required for expression of some members of the low-density lipoprotein (LDL) receptor family and is a universal ligand for member of the LDL-receptor family.
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